Epidemics of enterically transmitted non-A, non-B hepatitis (hepatitis E) have been reported in Asia, Africa, and North America. Similar cases of sporadic hepatitis, presumed to be hepatitis E, account for up to 90% of reported hepatitis in countries where hepatitis E is endemic. Hepatitis E virus (HEV) has been implicated in fulminant hepatitis of pregnancy. This disease has a 20% fatality rate. That a viral agent was responsible for hepatitis E epidemics was first shown in 1983. On the basis of electron microscopy and molecular characterization it was proposed that HEV belongs to the calicivirus family. The goal of this project is to define the newly identified hepatitis E virus (HEV), determine the extent and pattern of its involvement in enterically transmitted hepatitis, and to develop a vaccine which prevents hepatitis E. We performed a seroepidemiologic study which showed that HEV is a major cause of acute viral hepatitis in Saudi Arabia but that the cases are mainly in expatriates and not in Saudis. We found that rhesus mothers infected with HEV did not transmit the virus to their fetus in utero. Naturally acquired antibodies to HEV protected rhesus monkeys from hepatitis E after challenge with virulent virus. A vaccine composed of a processed form of ORF2 protein was highly efficacious in protecting cynomolgus monkeys from hepatitis E after challenge with a homologous virus strain or with the most divergent strain. The ORF-3 protein was tentatively identified as an RNA binding protein and a zinc binding protein.